# C/EBPβ Regulation of the Type 1 IFN Response; Sensitizing Keratinocytes to Direct Activators of Cytosolic PRRs and DNA Damage-Induced Cell Death

> **NIH NIH R01** · NORTH CAROLINA STATE UNIVERSITY RALEIGH · 2024 · $310,799

## Abstract

Cellular stress, DNA damage, pathogen insult, and immune mechanisms can activate molecular pathways that
result in regulated cell death. Increasing our understanding of the pathways that regulate cell death decisions
in response to cellular stress is critical as misregulated cell death is linked to cancer, neurodegeneration and
autoimmune diseases. The epidermis is the first line of defense to cutaneous microbes, viruses and
environmental insults, and keratinocytes play a critical role in the host innate immune response mediated by
type I interferons (IFN-I). In addition to anti-microbial and anti-viral responses this same IFN-I response also
mediates diverse cellular and biological responses such as proliferation, apoptosis, senescence and the DNA
damage response. Recent data from out laboratory suggest that the CCAAT/enhancer-binding protein-β
(C/EBPβ) transcription factor is a novel regulator the keratinocyte type IFN-I response. We observed the
conditional deletion of C/EBPβ in mouse epidermis (CKOβ) resulted in increased expression of IFNb and
numerous ISGs which included cytosolic pattern recognition receptors (cPRRs). cPRRs sense viral/pathogen
RNA and DNA as well as damaged host cytosolic DNA and RNA to trigger a IFN-I response. CKOβ
keratinocytes treated with direct activators of cytosolic PRRs displayed a greatly increased IFN-I response that
surprisingly resulted in increased apoptosis via the activation of caspase-8 and caspase-3. As breifly
mentioned, DNA damage can activate the innate immune response. DNA damaging agents can result in
modifications and structural changes in RNA and DNA that could potentially be sensed by cytosolic PRRs. We
observed that CKOβ keratinocytes challenged with DNA damage displayed increase caspase 8-mediated
apoptosis that was dependent on the interferon a/b receptor (INFAR). Activation of a type IFN-I response can
result in the increased expression of ISGs with apoptotic functions that activate caspase-8 mediated apoptosis
via death receptor signaling. The objective of this proposal is to understand molecular basis for how C/EBPβ
negatively regulates the IFN-I response and caspase-8 mediated apoptosis in response to direct activators of
cytosolic PRRs and DNA damage in vivo in mouse epidermis and in primary keratinocytes. We hypothesize
that C/EBPβ negatively regulates the IFN-I response in keratinocytes and the loss of C/EBPβ sensitizes
keratinocytes to the direct activation of cytosolic PRRs by pathogen RNA/DNA or damaged host RNA/DNA to
induce pro-apoptotic ISGs and caspase 8-mediated apoptosis. These experiments will increase our
understanding of a novel pathway by which C/EBPβ regulates activation of cPRRs and the IFN-I response to
control cell death decisions in response to cellular stress including DNA damage. This increased
understanding could identify new therapeutic targets to restore proper regulation of cell death to treat skin
cancer, skin infectious diseases, and skin autoimmune diseases.

## Key facts

- **NIH application ID:** 10886136
- **Project number:** 5R01AR081974-02
- **Recipient organization:** NORTH CAROLINA STATE UNIVERSITY RALEIGH
- **Principal Investigator:** Jonathan Russell Hall
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $310,799
- **Award type:** 5
- **Project period:** 2023-07-15 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10886136

## Citation

> US National Institutes of Health, RePORTER application 10886136, C/EBPβ Regulation of the Type 1 IFN Response; Sensitizing Keratinocytes to Direct Activators of Cytosolic PRRs and DNA Damage-Induced Cell Death (5R01AR081974-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10886136. Licensed CC0.

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